Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African Ancestry Anthropometry Genetics Consortium

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  • Ng, Maggie C. Y.
    • Other Affiliation: Center for Genomics and Personalized Medicine Research; Wake Forest School of Medicine
  • Graff, Mariaelisa
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Lu, Yingchang
    • Other Affiliation: The Charles Bronfman Institute for Personalized Medicine; Icachn School of Medicine at Mount Sinai
  • Justice, Anne E.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Mudgal, Poorva
    • Other Affiliation: Center for Diabetes Research; Wake Forest School of Medicine
  • Liu, Ching-Ti
    • Other Affiliation: Department of Biostatistics; Boston University School of Public Health
  • Young, Kristin
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Yanek, Lisa R.
    • ORCID: 0000-0001-7117-1075
    • Other Affiliation: Department of Medicine; Johns Hopkins University School of Medicine
  • Feitosa, Mary F.
    • Other Affiliation: Division of Statistical Genomics; Department of Genetics; Washington University School of Medicine
  • Wojczynski, Mary K.
    • ORCID: 0000-0002-2420-162X
    • Other Affiliation: Division of Statistical Genomics; Department of Genetics; Washington University School of Medicine
  • Rand, Kristin
    • Other Affiliation: Department of Preventive Medicine; Keck School of Medicine; University of Southern California
  • Brody, Jennifer A.
    • ORCID: 0000-0001-8509-148X
    • Other Affiliation: Cardiovascular Health Research Unit; Department of Medicine; University of Washington
  • Cade, Brian E.
    • Other Affiliation: Division of Sleep and Circadian Disorders; Brigham and Women's Hospital
  • Dimitrov, Latchezar
    • Other Affiliation: Center for Genomics and Personalized Medicine Research; Wake Forest School of Medicine
  • Duan, Qing
    • Affiliation: School of Medicine, Department of Genetics
  • Guo, Xiuqing
    • Other Affiliation: Institute for Translational Genomics and Population Sciences; Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
  • Lange, Leslie A.
    • Affiliation: School of Medicine, Department of Genetics
  • Nalls, Michael A.
    • Other Affiliation: Laboratory of Neurogenetics; National Institute on Aging; National Institutes of Health
  • Okut, Hayrettin
    • Other Affiliation: Center for Diabetes Research; Wake Forest School of Medicine
  • Tajuddin, Salman M.
    • ORCID: 0000-0002-7919-8528
    • Other Affiliation: National Institute on Aging; National Institutes of Health
  • Tayo, Bamidele O.
    • Other Affiliation: Department of Public Health Sciences; Stritch School of Medicine; Loyola University Chicago
  • Vedantam, Sailaja
    • Other Affiliation: Broad Institute of MIT and Harvard
  • Bradfield, Jonathan P.
    • Other Affiliation: Center for Applied Genomics; The Children’s Hospital of Philadelphia
  • Chen, Guanjie
    • Other Affiliation: Center for Research on Genomics and Global Health; National Human Genome Research Institute; National Institutes of Health
  • Chen, Wei-Min
    • ORCID: 0000-0002-2643-2333
    • Other Affiliation: Department of Public Health Sciences and Center for Public Health Genomics; University of Virginia School of Medicine
  • Chesi, Alessandra
    • Other Affiliation: Division of Human Genetics; The Children’s Hospital of Philadelphia
  • Irvin, Marguerite R.
    • Other Affiliation: Department of Epidemiology; University of Alabama at Birmingham
  • Padhukasahasram, Badri
    • Other Affiliation: Center for Health Policy and Health Services Research; Henry Ford Health System
  • Smith, Jennifer A.
    • ORCID: 0000-0002-3575-5468
    • Other Affiliation: Department of Epidemiology; University of Michigan
  • Zheng, Wei
    • Other Affiliation: Division of Epidemiology; Department of Medicine; Vanderbilt Epidemiology Center; Vanderbilt University School of Medicine
  • Allison, Matthew A.
    • Other Affiliation: Division of Preventive Medicine; Department of Family Medicine and Public Health; University of California San Diego
  • Ambrosone, Christine B.
    • Other Affiliation: Department of Cancer Prevention and Control; Roswell Park Cancer Institute
  • Bandera, Elisa V.
    • Other Affiliation: Department of Population Science; Rutgers Cancer Institute of New Jersey
  • Bartz, Traci M.
    • ORCID: 0000-0003-3403-8763
    • Other Affiliation: Cardiovascular Health Research Unit; Departments of Medicine and Biostatistics; University of Washington
  • Berndt, Sonja I.
    • Other Affiliation: Division of Cancer Epidemiology and Genetics; National Cancer Institute
  • Bernstein, Leslie
    • ORCID: 0000-0002-7692-6518
    • Other Affiliation: Beckman Research Institute of the City of Hope
  • Blot, William J.
    • Other Affiliation: International Epidemiology Institute
  • Bottinger, Erwin P.
    • Other Affiliation: The Charles Bronfman Institute for Personalized Medicine; Icachn School of Medicine at Mount Sinai
  • Carpten, John
    • Other Affiliation: Department of Translational Genomics; Keck School of Medicine; University of Southern California
  • Chanock, Stephen J.
    • Other Affiliation: Division of Cancer Epidemiology and Genetics; National Cancer Institute
  • Chen, Yii-Der Ida
    • Other Affiliation: Institute for Translational Genomics and Population Sciences; Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
  • Conti, David V.
    • Other Affiliation: Department of Preventive Medicine; Keck School of Medicine; University of Southern California
  • Cooper, Richard S.
    • Other Affiliation: Department of Public Health Sciences; Stritch School of Medicine; Loyola University Chicago
  • Fornage, Myriam
    • Other Affiliation: Center for Human Genetics; University of Texas Health Science Center at Houston
  • Freedman, Barry I.
    • Other Affiliation: Department of Internal Medicine; Wake Forest School of Medicine
  • Garcia, Melissa
    • Other Affiliation: National Institute on Aging; National Institutes of Health
  • Goodman, Phyllis J.
    • Other Affiliation: SWOG Statistical Center; Fred Hutchinson Cancer Research Center
  • Hsu, Yu-Han H.
    • Other Affiliation: Broad Institute of MIT and Harvard
  • Hu, Jennifer
    • Other Affiliation: Department of Public Health Sciences; University of Miami Leonard Miller School of Medicine
  • Huff, Chad D.
    • Other Affiliation: Department of Epidemiology; University of Texas M.D. Anderson Cancer Center
  • Ingles, Sue A.
    • Other Affiliation: Norris Comprehensive Cancer Center; University of Southern California
  • John, Esther M.
    • Other Affiliation: Department of Health Research and Policy (Epidemiology) and Stanford Cancer Institute; Stanford University School of Medicine
  • Kittles, Rick
    • Other Affiliation: Division of Urology; Department of Surgery; The University of Arizona
  • Klein, Eric
    • Other Affiliation: Glickman Urological and Kidney Institute; Cleveland Clinic
  • Li, Jin
    • Other Affiliation: Division of Cardiovascular Medicine; Department of Medicine; Stanford University School of Medicine
  • McKnight, Barbara
    • Other Affiliation: Cardiovascular Health Research Unit; Department of Biostatistics; University of Washington
  • Nayak, Uma
    • Other Affiliation: Center for Public Health Genomics; University of Virginia School of Medicine
  • Nemesure, Barbara
    • Other Affiliation: Department of Preventive Medicine; Stony Brook University
  • Ogunniyi, Adesola
    • ORCID: 0000-0002-2946-8956
    • Other Affiliation: Department of Medicine; University of Ibadan
  • Olshan, Andrew
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
    • Other Affiliation: University of North Carolina at Chapel Hill
  • Press, Michael F.
    • ORCID: 0000-0003-3400-6614
    • Other Affiliation: Department of Pathology and Norris Comprehensive Cancer Center; University of Southern California Keck School of Medicine
  • Rohde, Rebecca
    • ORCID: 0000-0001-5339-9535
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Rybicki, Benjamin A.
    • ORCID: 0000-0003-3190-3467
    • Other Affiliation: Department of Public Health Sciences; Henry Ford Health System
  • Salako, Babatunde
    • Other Affiliation: Department of Medicine; University of Ibadan
  • Sanderson, Maureen
    • Other Affiliation: Department of Family and Community Medicine; Meharry Medical College
  • Shao, Yaming
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Siscovick, David S.
    • Other Affiliation: The New York Academy of Medicine
  • Stanford, Janet L.
    • Other Affiliation: Department of Epidemiology; School of Public Health; University of Washington
  • Stevens, Victoria L.
    • ORCID: 0000-0003-0259-4407
    • Other Affiliation: Epidemiology Research Program; American Cancer Society
  • Stram, Alex
    • ORCID: 0000-0002-8278-6507
    • Other Affiliation: Department of Preventive Medicine; Keck School of Medicine; University of Southern California
  • Strom, Sara S.
    • Other Affiliation: Department of Epidemiology; University of Texas M.D. Anderson Cancer Center
  • Vaidya, Dhananjay
    • Other Affiliation: Department of Epidemiology; Bloomberg School of Public Health
  • Witte, John S.
    • Other Affiliation: Institute for Human Genetics; University of California; San Francisco
  • Yao, Jie
    • Other Affiliation: Institute for Translational Genomics and Population Sciences; Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
  • Zhu, Xiaofeng
    • Other Affiliation: Department of Epidemiology and Biostatistics; Case Western Reserve University
  • Ziegler, Regina G.
    • Other Affiliation: Division of Cancer Epidemiology and Genetics; National Cancer Institute; National Institutes of Health
  • Zonderman, Alan B.
    • Other Affiliation: National Institute on Aging; National Institutes of Health
  • Adeyemo, Adebowale
    • ORCID: 0000-0002-3105-3231
    • Other Affiliation: Center for Research on Genomics and Global Health; National Human Genome Research Institute; National Institutes of Health
  • Ambs, Stefan
    • Other Affiliation: Laboratory of Human Carcinogenesis; National Cancer Institute
  • Cushman, Mary
    • Other Affiliation: Department of Medicine; University of Vermont College of Medicine
  • Faul, Jessica D.
    • Other Affiliation: Survey Research Center; Institute for Social Research; University of Michigan
  • Hakonarson, Hakon
    • Other Affiliation: Department of Pediatrics; Perelman School of Medicine; University of Pennsylvania
  • Levin, Albert M.
    • Other Affiliation: Department of Public Health Sciences; Henry Ford Health System
  • Nathanson, Katherine L.
    • Other Affiliation: Department of Medicine; University of Pennsylvania
  • Ware, Erin B.
    • Other Affiliation: Survey Research Center; Institute for Social Research; University of Michigan
  • Weir, David R.
    • Other Affiliation: Survey Research Center; Institute for Social Research; University of Michigan
  • Zhao, Wei
    • ORCID: 0000-0002-4032-5745
    • Other Affiliation: Department of Epidemiology; University of Michigan
  • Zhi, Degui
    • Other Affiliation: School of Biomedical Informatics; University of Texas Health Science Center at Houston
  • Arnett, Donna K.
    • Other Affiliation: School of Public Health; University of Kentucky
  • Grant, Struan F. A.
    • Other Affiliation: Department of Pediatrics; Perelman School of Medicine; University of Pennsylvania
  • Kardia, Sharon L. R.
    • Other Affiliation: Department of Epidemiology; University of Michigan
  • Oloapde, Olufunmilayo I.
    • Other Affiliation: Center for Clinical Cancer Genetics; Department of Medicine and Human Genetics; University of Chicago
  • Rao,
    • Other Affiliation: Division of Biostatistics; Washington University School of Medicine
  • Rotimi, Charles N.
    • ORCID: 0000-0001-5759-053X
    • Other Affiliation: Center for Research on Genomics and Global Health; National Human Genome Research Institute; National Institutes of Health
  • Sale, Michele M.
    • ORCID: 0000-0003-1644-9040
    • Other Affiliation: Department of Public Health Sciences and Center for Public Health Genomics; University of Virginia School of Medicine
  • Williams, L. Keoki
    • Other Affiliation: Center for Health Policy and Health Services Research; Henry Ford Health System
  • Zemel, Babette S.
    • Other Affiliation: Department of Pediatrics; Perelman School of Medicine; University of Pennsylvania
  • Becker, Diane M.
    • Other Affiliation: Department of Medicine; Johns Hopkins University School of Medicine
  • Borecki, Ingrid B.
    • Other Affiliation: Regeneron Genetics Center; Regeneron Pharmaceuticals; Inc
  • Evans, Michele K.
    • Other Affiliation: National Institute on Aging; National Institutes of Health
  • Harris, Tamara B.
    • Other Affiliation: National Institute on Aging; National Institutes of Health
  • Hirschhorn, Joel N.
    • Other Affiliation: Broad Institute of MIT and Harvard
  • Li, Yun
    • Affiliation: School of Medicine, Department of Genetics
    • Other Affiliation: Department of Computer Science
  • Patel, Sanjay R.
    • ORCID: 0000-0002-9142-5172
    • Other Affiliation: Department of Medicine; University of Pittsburgh
  • Psaty, Bruce M.
    • Other Affiliation: Cardiovascular Health Research Unit; Departments of Medicine; Epidemiology; and Health Services; University of Washington
  • Rotter, Jerome I.
    • Other Affiliation: Division of Genomic Outcomes; Departments of Pediatrics and Medicine; Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
  • Wilson, James G.
    • Other Affiliation: Department of Physiology and Biophysics; University of Mississippi Medical Center
  • Bowden, Donald W.
    • Other Affiliation: Center for Genomics and Personalized Medicine Research; Wake Forest School of Medicine
  • Cupples, L. Adrienne
    • Other Affiliation: NHLBI Framingham Heart Study
  • Haiman, Christopher A.
    • Other Affiliation: Norris Comprehensive Cancer Center; University of Southern California
  • Loos, Ruth J. F.
    • Other Affiliation: The Charles Bronfman Institute for Personalized Medicine; Icachn School of Medicine at Mount Sinai
  • North, Kari E.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
Abstract
  • Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10−8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.
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DOI
Identifier
Resource type
  • Article
Rights statement
  • In Copyright
Journal title
  • PLoS Genetics
Journal volume
  • 13
Journal issue
  • 4
Page start
  • e1006719
Language
  • English
ISSN
  • 1553-7390
  • 1553-7404

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